The present invention, in some embodiments thereof, relates to methods and compositions for treating angiogenesis-related diseases such as cancer, and methods of selection thereof.
The neuropilin-1 (np1) and the neuropilin-2 (np2) receptors were originally characterized as functional receptors for axon guidance factors belonging to the class-3 semaphorin (sema3) family. It was subsequently realized that the neuropilins are expressed by endothelial cells and by many types of cancer cells. It was also found that the neuropilins function in addition as receptors for several angiogenic factors belonging to the VEGF family and as receptors for the angiogenesis/metastasis inducing growth factor hepatocyte growth factor/scatter factor (HGF/SF), and that they function as potent enhancers of their pro-angiogenic activity.
Most of the sema3s, with the exception of sema3E which binds to PlexD1, bind to one of the two neuropilin receptors or to both. Neuropilins form spontaneous complexes with several members of the plexin receptor family. In these complexes the sema3s bind to neuropilins while the plexins function as the signal transducing elements. The four type-A plexins (plexins-A1 to plexin-A4) as well as plexin-D1 form complexes with neuropilins and participate in neuropilin mediated signal transduction.
Semaphorins sema3B and sema3F were also characterized as tumor suppressors whose loss contributes to the development of lung cancer [Tomizawa, Y., 2001, Proc. Natl. Acad. Sci. U.S.A 98:13954-13959; Xiang, R., 2002. Cancer Res. 62:2637-2643].
The identification of neuropilins in endothelial cells suggested that class-3 semaphorins may be able to regulate angiogenesis. Indeed, the class-3 semaphorin sema3F, a np2 agonist, functions as a repellant of endothelial cells, induces apoptosis of endothelial cells upon prolonged stimulation [Bielenberg, D. R., et al., 2004, J. Clin. Invest 114:1260-1271; Guttmann-Raviv, N., et al., 2007, J. Biol. Chem. 282:26294-26305] and inhibits angiogenesis and tumor progression in-vivo Mielenberg, D. R., et al., 2004, J. Clin. Invest 114:1260-1271; Kessler, O., et al 2004. Cancer Res. 64:1008-1015. The np1 agonist sema3A was also shown to inhibit in-vitro and in-vivo angiogenesis [Miao, H. Q., 1999. J. Cell Biol. 146:233-242. Bates, D., 2003, Dev. Biol. 255:77-98; Acevedo, L. M., 2008. Blood. 111:2674-2680]. Sema3E was also characterized as a repulsive agent that inhibits the invasion of PlexD1 expressing blood vessels into somites during embryonic development [Gu C. et al., 2005, Science 307:265-268].
In contrast, existing data suggests that sema3C functions as a pro-tumorigenic and pro-angiogenic agent [Herman J G, et al, Int. J. Oncol. 2007; 30:1231-1238; Banu N, FASEB J. 2006; 20:2150-2152].
The fact that neuropilins and plexins such as PlexD1 are also expressed by many types of tumor cells indicates that semaphorins may also affect the behavior of tumor cells directly. Indeed, sema3s such as sema3F and sema3B have been observed to inhibit the adhesion, migration or the proliferation of tumor cells expressing appropriate semaphorin receptors [Tomizawa, Y., 2001, Proc. Natl. Acad. Sci. U.S.A 98:13954-13959; Xiang, R., 2002. Cancer Res. 62:2637-2643; Bielenberg, D. R., et al., 2004, J. Clin. Invest 114:1260-1271; Nasarre, 2006, Neoplasia. 7:180-189]. In contrast, however, the cleavage product of Sema3E, was shown to be an inducer of tumor invasiveness and tumor metastasis [Christensen, C, 2005, Cancer Res. 65, 6167-6177].